Interleukin (IL)-17 has emerged to be a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA) and arthritis models. CD4+T cells producing IL-17 has recently been identified as a distinct subset of Th cells and designated Th17. The differentiation of Th17 subset from naive CD4+ T cells requires stimulation in the presence of IL-6 and transforming growth factor (TGF)-p. IL-23 is required for Th17 clonal expansion. Interferon (IFN)-y, IL-4, IL-27, IL-25 and IL-2 negatively regulate Th17 development. Our preliminary studies in murine collagen-induced arthritis (CIA) model showed that in response to collagen type II (Cll) immunization, CIA resistant C57BL/6 (B6) mice expressed high IFN-y and low IL-17 while CIA susceptible DBA/1 mice expressed low IFN-y and high IL-17. Moreover, IFN-y suppressed Cll stimulated IL-17 production. IFN-y knockout B6 mice displayed significantly enhanced IL-17 response and developed CIA that was mediated by IL-17. RORyt is an orphan nuclear hormone receptor that has been implicated as master transcription factor for IL-17. We showed that overexpression of RORyt markedly increased IL-17 production by CD4+ T cells. The goals of this proposal are to define the mechanisms of IFN-y mediated suppression of IL-17 and factors positively regulate IL-17 production during arthritis. We plan to investigate the mechanisms for low IFN-y response in DBA/1 mice and cellular and molecular mechanisms of IFN-y mediated suppression of IL-17 by focusing on effects of IFN^y on RORyt expression and binding to IL-17 gene promoter. Finally, using RORyt transgenic mice and Cll TCR transgenic mice we will examine what cytokines are required for development of arthritogenic Th17 cells and arthritis expression and chronicity. Understanding the details of how arthritogenic Th17 cells are regulated during arthritis models will provide useful information for novel therapeutic design in RA by targeting factors regulating IL-17 expression. [unreadable] [unreadable] [unreadable] [unreadable]